Protect cells from phase I oestrogen metabolites

Protecting cells from phase I dangerous oestrogen metabolites is very important as they are directly involved in DNA adduct formation and breast carcinogenesis. These are Resveratrol, N-acetylcysteine and berries.

There is much data to support the role of Resveratrol in protecting against 4-OH E2. To summarise, the protective properties of Resveratrol are three-fold32:

  • ■ The inhibition of CYP1B1 expression, which decreases the formation of 4-OH E2 that should be further methylated
  • ■ The induction of NQO1 enzyme, that provides a decrease in oestrogen quinones and an increase in catechol oestrogen
  • ■ The antioxidant properties of Resveratrol reduce oestrogen semiquinones to catechol oestrogens, as indirectly determined in vitro.

One must make sure that Resveratrol is prescribed while methylation is supported. Therefore, all patients with CYP1B1 increase predictive activity should receive Resveratrol with supported methylation. If COMT is present and unhealthy methylation is suspected, it is important to promoted healthy levels of glutathione S-transverase (GST). GST SNP results in decreased detoxifying capacity of dangerous oestrogen quinones. Nutritional support could be achieved with alpha-lipoic acid, whey protein, vitamin C, Sylimarin and cruciferous vegetables (I3C).

N-acetylcysteine blocks the formation of cancer-initiating oestrogen–DNA adducts in cells, and could be used as a potential chemopreventive agent to block the initial step in the genotoxicity caused by catechol oestrogen quinones33, 34.

Promote healthy methylation

Supporting healthy methylation is vital during HRT for the prevention of breast cancer and endometrial cancer. The COMT enzyme is involved in the detoxification of dangerous catechol oestrogen metabolites and biotransformation into neutral and protective methoxylated metabolites. In fact, it is not recommended to prescribe any hormonal substitution in cases of homozygous genetic variants of COMT SNP, where there is a total decreased enzyme activity. In heterozygous genetic variants, the smallest possible dose of weak oestrogen over a short period of time — preferably bioidentical hormone in transdermal application — should be used together with supplements supporting methylation (e.g. vitamin B6, vitamin B12, choline, trimethylglycine (TMG), and folic acid). The potential genetic polymorphism of 5-MTHFR should also be ruled out, as folate in the form of L-5-MTHF is paramount for the synthesis of S-Adenosyl methionine (SAM; a methyl donor for the methylation of DNA). One should have a good overview of methylation activity by carrying out genetic testing for COMT and MTHFR SNPs, and checking homocysteine levels.

Encourage healthy intestinal excretion

Checking UGT SNP for glucuronidation is not as important as supporting the healthy intestinal excretion of oestrogens and decreasing the enterohepatic circulation of oestrogens by eliminating the action of β-glucuronidase, by adding dietary fibre, phytoestrogens and probiotics.

Balance

Environmental xenobiotics are ‘endocrine disruptors’ that modify intercellular communication and function. They produce a higher amount of the 4-OH and 16a-OH oestrogen metabolites that are potentially more genotoxic by modifying members of the CYP450 enzyme family (especially CYP1A1, CYP1B1 and GST). Xenobiotics can change DNA methylation (epigenetic modification), which can ultimately change oestrogen receptor activity. This may play a role in cancer pathology. A variety of pesticides have been shown in vitro to influence aromatase activity, increasing oestrogen conversion from androgens and adding an extra oestrogen burden in the body35.

High organochlorine levels promote high proliferation in oestrogen receptor-α positive breast cancers in postmenopausal women. All oestrogen receptor-α positive breast carcinomas from postmenopausal women had high cellular proliferation when levels of organochlorine residues were 2600 ppb or higher36. All patients of HRT should have a serological markers for toxicity checked, a toxicity questionnaire and SNP identification (Femgen), and prior to any HRT, the elimination of environmental xenobiotics should be implemented.

Conclusions

Conventional HRT, prescribed as ‘one-size-fits-all’, created a fear of breast cancer in patients and an uncomfortable decision for physicians who could not precisely estimate the risks described in the literature. By identifying women’s individual oestrogen metabolism and estimating the production of dangerous oestrogen metabolites in a particular case, it is possible to obtain a better picture of the actual risk.